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Title: Heterodimerization of Retinoid X Receptor with Xenobiotic Receptor partners occurs in the cytoplasmic compartment: Mechanistic insights of events in living cells

Abstract

Retinoid X Receptor (RXR) serves as the heterodimeric partner of two major xenobiotic nuclear receptors, Pregnane and Xenobiotic Receptor (PXR) and Constitutive Androstane Receptor (CAR). These receptors are primarily involved in the metabolism and clearance of endobiotics and xenobiotics (including clinical drugs) from the body. Here, we report for the first time that intermolecular interactions between RXR-PXR and RXR-CAR occurs in the cytoplasmic compartment of the cell in a ligand-independent manner. These interactions lead to nuclear import of the heterodimeric complex thereby making them competent for chromatin binding and transactivation of target genes. To explore the cellular site involved in the process of heterodimerization we created various RFP- and GFP-tagged receptor chimeras and also the mutants of their nuclear localization signal (NLS). From the study it is apparent that NLS of PXR/CAR/RXR play a major role in the import of the heterodimeric complex from the cytoplasm to the nucleus in a ligand-independent manner. We observed that along with the heterodimeric partner and/or respective ligand a functional NLS is necessary for activation of target gene. The data suggests that RXR is the major driving force to import the heterodimeric complex into the nucleus since the mutation in the NLS region ofmore » RXR weakens this import process dramatically, whereas mutations in the NLS regions of PXR and CAR have little or no significant effect. This RXR-dependent nuclear translocation of the heterodimeric complex also modulates the individual transcriptional activity of PXR and CAR by increasing the basal transcriptional activity. Finally, it is documented that the heterodimerization of RXR with both the partners (PXR, CAR) occurs in the cytoplasm and implies that these dynamic interactions have functional and regulatory attributes in gene expression. In addition, this RXR-dependent enhancement of the transcriptional activity of PXR and CAR may be utilized for evaluating the receptor-drug interactions. - Highlights: • RFP-tagged RXR, PXR and CAR are used to study receptor heterodimerization. • Tagged receptors shifted to cytoplasm and imported to nucleus after heterodimerization. • Wild-type nuclear receptor can translocate cytoplasmic NLS-mutant to the nucleus. • Receptor heterodimerization is a ligand-independent event and occurs in cytoplasm. • Transcriptional activity of nuclear receptor is enhanced by heterodimerization.« less

Authors:
; ; ;
Publication Date:
OSTI Identifier:
22738189
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 360; Journal Issue: 2; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CELL NUCLEI; COMPARTMENTS; COMPLEXES; CYTOPLASM; GENES; INTERACTIONS; MUTANTS; MUTATIONS; RECEPTORS; TRANSCRIPTION; XENOBIOTICS

Citation Formats

Dash, Amit K., Yende, Ashutosh S., Jaiswal, Bharti, and Tyagi, Rakesh K., E-mail: rktyagi@yahoo.com. Heterodimerization of Retinoid X Receptor with Xenobiotic Receptor partners occurs in the cytoplasmic compartment: Mechanistic insights of events in living cells. United States: N. p., 2017. Web. doi:10.1016/J.YEXCR.2017.09.024.
Dash, Amit K., Yende, Ashutosh S., Jaiswal, Bharti, & Tyagi, Rakesh K., E-mail: rktyagi@yahoo.com. Heterodimerization of Retinoid X Receptor with Xenobiotic Receptor partners occurs in the cytoplasmic compartment: Mechanistic insights of events in living cells. United States. doi:10.1016/J.YEXCR.2017.09.024.
Dash, Amit K., Yende, Ashutosh S., Jaiswal, Bharti, and Tyagi, Rakesh K., E-mail: rktyagi@yahoo.com. Wed . "Heterodimerization of Retinoid X Receptor with Xenobiotic Receptor partners occurs in the cytoplasmic compartment: Mechanistic insights of events in living cells". United States. doi:10.1016/J.YEXCR.2017.09.024.
@article{osti_22738189,
title = {Heterodimerization of Retinoid X Receptor with Xenobiotic Receptor partners occurs in the cytoplasmic compartment: Mechanistic insights of events in living cells},
author = {Dash, Amit K. and Yende, Ashutosh S. and Jaiswal, Bharti and Tyagi, Rakesh K., E-mail: rktyagi@yahoo.com},
abstractNote = {Retinoid X Receptor (RXR) serves as the heterodimeric partner of two major xenobiotic nuclear receptors, Pregnane and Xenobiotic Receptor (PXR) and Constitutive Androstane Receptor (CAR). These receptors are primarily involved in the metabolism and clearance of endobiotics and xenobiotics (including clinical drugs) from the body. Here, we report for the first time that intermolecular interactions between RXR-PXR and RXR-CAR occurs in the cytoplasmic compartment of the cell in a ligand-independent manner. These interactions lead to nuclear import of the heterodimeric complex thereby making them competent for chromatin binding and transactivation of target genes. To explore the cellular site involved in the process of heterodimerization we created various RFP- and GFP-tagged receptor chimeras and also the mutants of their nuclear localization signal (NLS). From the study it is apparent that NLS of PXR/CAR/RXR play a major role in the import of the heterodimeric complex from the cytoplasm to the nucleus in a ligand-independent manner. We observed that along with the heterodimeric partner and/or respective ligand a functional NLS is necessary for activation of target gene. The data suggests that RXR is the major driving force to import the heterodimeric complex into the nucleus since the mutation in the NLS region of RXR weakens this import process dramatically, whereas mutations in the NLS regions of PXR and CAR have little or no significant effect. This RXR-dependent nuclear translocation of the heterodimeric complex also modulates the individual transcriptional activity of PXR and CAR by increasing the basal transcriptional activity. Finally, it is documented that the heterodimerization of RXR with both the partners (PXR, CAR) occurs in the cytoplasm and implies that these dynamic interactions have functional and regulatory attributes in gene expression. In addition, this RXR-dependent enhancement of the transcriptional activity of PXR and CAR may be utilized for evaluating the receptor-drug interactions. - Highlights: • RFP-tagged RXR, PXR and CAR are used to study receptor heterodimerization. • Tagged receptors shifted to cytoplasm and imported to nucleus after heterodimerization. • Wild-type nuclear receptor can translocate cytoplasmic NLS-mutant to the nucleus. • Receptor heterodimerization is a ligand-independent event and occurs in cytoplasm. • Transcriptional activity of nuclear receptor is enhanced by heterodimerization.},
doi = {10.1016/J.YEXCR.2017.09.024},
journal = {Experimental Cell Research},
issn = {0014-4827},
number = 2,
volume = 360,
place = {United States},
year = {2017},
month = {11}
}